US 7,351,727 B2Granted

Inhibitors of 15-lipoxygenase

AssigneeBristol-Myers Squibb Company

InventorDavid S. Weinstein

Life of this patent

Estimating the term…

Abstract

The present invention provides oxazolyl and thiazolyl inhibitors of 15-LO, pharmaceutical compositions containing such inhibitors and methods for treating diseases related to the 15-LO cascade using such compounds and compositions.

Claims4

Dependent claims

A compound according to Formula I

including enantiomers, diastereomers, salts and solvates thereof, wherein:
X is S;
J1 is a bond, —C(O)—, —OC(O)—, —C(O)O—, —NR4—, —NR4—C(O)—, or —C(O)NR4—;
J2 is a bond, —C(O)—, —OC(O)—, —C(O)O—, —NR4a—, NR4a—C(O)—, or C(O)NR4a—;
J3 is alkylene, cycloalkylene, alkenylene or alkynylene each of which may be optionally substituted with T1a, T2a and T3a;
M is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally substituted with T1b, T2b and T3b;
R1 is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally substituted with T1c, T2c and T3c;
R2 is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally substituted with T1d, T2d and T3d;
R3 is —NR3aSO2Z, —NR3aC(O)OZ, —NR3aC(O)Z, —NR3aC(O)NR3bZ, or
R3a, R3b, R4, and R4a are each independently
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally independently substituted with T1e, T2e and T3e;
Z is
(1) —NR5R6;
or
(2) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl, each of which may be optionally substituted with T1f, T2f and T3f;
R5 and R6 are independently
(1) hydrogen;
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally independently substituted with T1g, T2g and T3g;
or
(3) —C(O)R7, —C(O)OR7, or —OC(O)R7;
or R5 and R6 together with the nitrogen atom to which they are bonded can combine to form a 5 to 12-membered heterocyclo ring optionally substituted with T1g, T2g and T3g;
R7 is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally independently substituted with T1h, T2h and T3h;
T1a-1h, T2a-2h, and T3a-3h are optional substituents independently selected from
(1) V, where V is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1,
(2) —OH or —OV,
(3) —SH or —SV,
(4) —C(O)tH, —C(O)tV, or —O—C(O)V, where t is 1 or 2,
(5) —SO3H, —S(O)tV, or S(O)tN(V1)V,
(6) halo,
(7) cyano,
(8) nitro,
(9) —U1—NV2V3,
(10) —U1—N(V1)—U2—NV2V3,
(11) —U1—N(V4)—U2—V,
(12) —U1—N(V4)—U2—H,
(13) oxo;
U1 and U2 are each independently
(1) a single bond,
(2) —U3—S(O)t—U4—,
(3) —U3—C(O)—U4—,
(4) —U3—C(S)—U4—,
(5) —U3—O—U4—,
(6) —U3—S—U4—,
(7) —U3—O—C(O)—U4—,
(8) —U3—C(O)—O—U4—,
(9) —U3—C(═NV1a)—U4—, or
(10) —U3—C(O)—C(O)—U4—;
V1, V1a, V2, V3 and V4
(1) are each independently hydrogen or a group provided in the definition of T1;
or
(2) V2 and V3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T1, or
(3) V2 or V3, together with V1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T1, or
(4) V2 and V3 together with the nitrogen atom to which they are attached may combine to form a group —N═CV5V6 where V5 and V6 are each independently H or a group provided in the definition of V;
and
U3 and U4 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that
(1) groups —J1—R1 and —J2—R2 are not both hydrogen;
and
(2) when J1 is —NR4—,
(a) neither R1 or R4 are a cephalosporin group of formula
wherein
X is O, S, NR11, or CH2;
R8 is hydrogen or alkyl
R9 is alkyl optionally substituted with —OC(O)CH3 or —S—(tetrazolyl) wherein the tetrazole ring is optionally subtituted with alkyl;
R10 is COOH;
R11 is hydrogen, alkyl, formyl, or benzyl;
and
(b) R1 and R4 are not both hydrogen when —J2—R2 is hydrogen.

87 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/932,457Filed 1 Sep 2004 · us provisional application
Priority: 2 Sep 2003
Published: US 2005/0065198 A124 Mar 2005
Granted: 1 Apr 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 277/46
Acylated amino or imino radicals: by carboxylic acids, or sulfur or nitrogen analogues thereof
C07D 263/28
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 277/40
Nitrogen atoms: unsubstituted amino or imino radicals
C07D
Heterocyclic compounds

Family

Application60/499,438Us provisional application · filed 2 Sep 2003
US 2005/0065198 A1Pre-grant publication · published 24 Mar 2005
US 7,351,727 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound according to Formula I

including enantiomers, diastereomers, salts and solvates thereof, wherein:
X is S;
J1 is a bond, —C(O)—, —OC(O)—, —C(O)O—, —NR4—, —NR4—C(O)—, or —C(O)NR4—;
J2 is a bond, —C(O)—, —OC(O)—, —C(O)O—, —NR4a—, NR4a—C(O)—, or C(O)NR4a—;
J3 is alkylene, cycloalkylene, alkenylene or alkynylene each of which may be optionally substituted with T1a, T2a and T3a;
M is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally substituted with T1b, T2b and T3b;
R1 is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally substituted with T1c, T2c and T3c;
R2 is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally substituted with T1d, T2d and T3d;
R3 is —NR3aSO2Z, —NR3aC(O)OZ, —NR3aC(O)Z, —NR3aC(O)NR3bZ, or
R3a, R3b, R4, and R4a are each independently
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally independently substituted with T1e, T2e and T3e;
Z is
(1) —NR5R6;
or
(2) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl, each of which may be optionally substituted with T1f, T2f and T3f;
R5 and R6 are independently
(1) hydrogen;
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally independently substituted with T1g, T2g and T3g;
or
(3) —C(O)R7, —C(O)OR7, or —OC(O)R7;
or R5 and R6 together with the nitrogen atom to which they are bonded can combine to form a 5 to 12-membered heterocyclo ring optionally substituted with T1g, T2g and T3g;
R7 is
(1) hydrogen;
or
(2) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl each of which may be optionally independently substituted with T1h, T2h and T3h;
T1a-1h, T2a-2h, and T3a-3h are optional substituents independently selected from
(1) V, where V is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1,
(2) —OH or —OV,
(3) —SH or —SV,
(4) —C(O)tH, —C(O)tV, or —O—C(O)V, where t is 1 or 2,
(5) —SO3H, —S(O)tV, or S(O)tN(V1)V,
(6) halo,
(7) cyano,
(8) nitro,
(9) —U1—NV2V3,
(10) —U1—N(V1)—U2—NV2V3,
(11) —U1—N(V4)—U2—V,
(12) —U1—N(V4)—U2—H,
(13) oxo;
U1 and U2 are each independently
(1) a single bond,
(2) —U3—S(O)t—U4—,
(3) —U3—C(O)—U4—,
(4) —U3—C(S)—U4—,
(5) —U3—O—U4—,
(6) —U3—S—U4—,
(7) —U3—O—C(O)—U4—,
(8) —U3—C(O)—O—U4—,
(9) —U3—C(═NV1a)—U4—, or
(10) —U3—C(O)—C(O)—U4—;
V1, V1a, V2, V3 and V4
(1) are each independently hydrogen or a group provided in the definition of T1;
or
(2) V2 and V3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T1, or
(3) V2 or V3, together with V1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T1, or
(4) V2 and V3 together with the nitrogen atom to which they are attached may combine to form a group —N═CV5V6 where V5 and V6 are each independently H or a group provided in the definition of V;
and
U3 and U4 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that
(1) groups —J1—R1 and —J2—R2 are not both hydrogen;
and
(2) when J1 is —NR4—,
(a) neither R1 or R4 are a cephalosporin group of formula
wherein
X is O, S, NR11, or CH2;
R8 is hydrogen or alkyl
R9 is alkyl optionally substituted with —OC(O)CH3 or —S—(tetrazolyl) wherein the tetrazole ring is optionally subtituted with alkyl;
R10 is COOH;
R11 is hydrogen, alkyl, formyl, or benzyl;
and
(b) R1 and R4 are not both hydrogen when —J2—R2 is hydrogen.

87 more elements

Facts

Application

10/932,457Filed 1 Sep 2004 · us provisional application

Priority

2 Sep 2003

Published

US 2005/0065198 A124 Mar 2005

Granted

1 Apr 2008

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 277/46
Acylated amino or imino radicals: by carboxylic acids, or sulfur or nitrogen analogues thereof
C07D 263/28
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 277/40
Nitrogen atoms: unsubstituted amino or imino radicals
C07D
Heterocyclic compounds